The present invention relates to a compound which is usable in coatings for surfaces which come into contact with blood, in order to improve the hemocompatibility of the surface, and also to a coating of this kind and a medical device having at least one surface of this kind.
Compounds of this kind, coating compositions, and also methods for coating surfaces of medical devices are well known in the prior art.
In many medical treatments, use is made of medical devices of this kind which have plastics surfaces which come into contact with the blood of a patient over longer or shorter periods of time. These devices are, for example, disposable equipment for a heart-lung machine, oxygenators, dialyzers, ultrafilters, catheters, artificial organs such as heart or kidney, gas exchange membranes, or vascular prostheses, and this list is not to be understood as conclusive.
With all this medical equipment, the contact of blood which takes place with hydrophobic polymer surfaces activates various defense mechanisms in the blood. This is particularly true when conducting blood through dialyzers or ultrafilters which have hydrophilic membranes, but also when conducting blood through oxygenators having hydrophobic membranes and having large areas of defoamers, with the presence here of far higher flow velocities of the blood.
Here, not only the current-induced trauma but also, in particular, the properties of the plastics surfaces themselves are responsible for undesired reactions in the blood.
Adhesion of blood constituents to plastics surfaces and coagulation can occur, and this increases, firstly, the risk of malfunction of the equipment and, secondly, the risk of thrombosis. Furthermore, there occurs mainly an activation of blood constituents of the immune system, more particularly the complement system. Such an activation of the immune response is, however, disadvantageous, more particularly in view of the compromised health of the patients, and should therefore be prevented.
Therefore, for medical equipment and accessories which come into contact with blood, it is desirable to have available plastics surfaces which have a good blood compatibility.
Good blood compatibility, i.e. hemocompatibility, is generally understood to mean the property of a surface or substance such that the surface, upon contact with blood, activates neither blood coagulation nor the defense mechanisms of the body against the foreign surface or substance.
In order to achieve this, it is known to coat the plastics surfaces which come into contact with blood in such a way that these surfaces have an improved hemocompatibility.
It should be noted that, for example, dialyzer casings, oxygenators, and corresponding accessories are preferably made from clear polycarbonate, whose transparency and appearance must not be compromised by hydrophilizing coatings of this kind. It should be further noted that coatings of this kind are carried out before the sterilization of the corresponding medical equipment in order to reduce blood trauma during the use of industrially ready-made equipment. This is important against the background of there being a need for blood-compatible and sterile medical devices which can be kept in stock and are ready to use at any time and, in particular, in case of emergency.
In this connection, it is known, for example, to inhibit blood coagulation by a high-dose administration of heparin, or else to bind heparin to such surfaces which come into contact with blood.
It is further known to achieve a certain hemocompatibility of plastics surfaces by prerinsing with patients' blood or by coating with blood constituents of human, animal, or biotechnological origin.
Here, it is, in particular, albumin, which is a protein present in large amounts in the blood and which is rapidly adsorbed by the hydrophobic surfaces and then denatured on these surfaces, whereby the surfaces become hydrophilized.
It is further known to improve the hemocompatibility in or on medical equipment and/or accessories by coating plastics surfaces with synthetic surfactants.
However, the methods described in this respect all have certain disadvantages.
The inhibition of blood coagulation by means of heparin is contraindicated particularly in emergency medicine and especially in patients who may have mechanical or chemical traumas, since greater bleeding can occur as a result.
In the case of prerinsing with patients' blood, it is particularly disadvantageous that the coating can only be carried out immediately before the use of the devices to be thus coated. Thus, valuable time would be lost in emergency treatments, and this could lead to a considerable negative impact on the health of the patient. Furthermore, this treatment has the disadvantage that it can only be used within a very narrow time frame. Since the albumin taken up by the lipophilic surfaces during prerinsing of the device with patients' blood is easily displaced from said surfaces by other lipophilic substances, a continuous worsening of the hemocompatibility occurs.
Also, the denaturation of albumin at the lipophilic surfaces can lead to increased release of lipophilic substances bound to the albumin, such as medicaments or toxins, whereby the effects of medicaments used become more difficult to judge and toxic effects can occur. Furthermore, it is not possible with this method to control the coating quality.
In the case of coating with blood constituents of human or animal origin, more particularly the risk of infection is a factor which greatly impedes official approval of coatings of this kind. Furthermore, incompatibility reactions can occur in coatings of this kind.
Coating with constituents acquired by biotechnological methods is, in contrast, particularly disadvantageous because of the costs arising in connection with the acquisition and purification of these substances.
In order to address these problems and also the problems of approval with regard to albumin coatings, there is therefore a need for physiologically safe, novel coating materials for the hydrophilization of polymer surfaces, where the absence of viruses and other biological risk factors can also be assumed.
For the hemocompatible coating of plastics surfaces, use is therefore increasingly made of synthetic substances such as polymers or surfactants.
In this connection, U.S. Pat. No. 6,670,199 describes various coatings which comprise, as a basic structure, the surfactant Pluronic™, which can be conjugated with different biomolecules.
WO 2007/01994 showed that, although these coatings have antithrombogenic properties, they also result at the same time in a large deterioration in complement activation. The known coating thus does not have good blood compatibility. Furthermore, it has the disadvantage that the evenness of the coating is difficult to control.
A further requirement for coating methods is that, during operation of the medical equipment provided with correspondingly coated surfaces, leaching of coating material from the coated surfaces must not occur. Such a leaching might, in particular, induce toxic effects, such as the triggering of inflammatory reactions for example, after recirculation of the blood into the bloodstream of the patient.
It is known that synthetic substances in blood are almost always perceived as foreign and trigger defense mechanisms. The bonding of polyethylene oxide groups (PEO) to foreign molecules of this kind has a masking effect and is thus able to suppress immunological defense reactions. In this connection, WO 2007/019994 A1 discloses the use of certain ester surfactants in hemocompatible coatings of lipophilic surfaces. These ester surfactants have up to six long-chain fatty acid residues to which polyethylene oxide chains are bound. Because of these bound PEO radicals, the surfactants are soluble in water.
The immunological masking by PEO groups is also used in the production of artificial blood from hemoglobin of animal origin, as disclosed in, for example, WO 2002/000230 A1. For this purpose, exogenous substances are masked by attaching polyethylene oxide chains, whereby the triggering of the immune response can be reduced.
From the above-mentioned WO 2007/019994 A1, it is known that a reduced complement activation compared with Pluronic™ can be achieved using one of the ester surfactants described, which is sold as Cremophor™, owing to the combination of a large lipophilic molecular moiety, which allows a relatively strong adhesion to lipophilic surfaces via van der Waals forces, with attached PEO chains, which mask the substance from the components of the immune response.
In house comparative experiments have shown, however, that changes occur even in blood which comes into contact with Cremophor™-coated surfaces, compared with identical human blood which has not been exposed to surfaces, which changes indicate a strong activation of components of the immune system.
Against this background, an object of the present invention is therefore to provide a new class of compounds which can be used in coatings for surfaces which come into contact with blood and which have improved hemocompatible properties compared with known compounds.